Este estudo teve como hipótese que a expressão gênica para ADAM10 e miRNAs em amostras de sangue encontram-se alteradas em idosos com DA em comparação a idosos sem alteração cognitiva.
Sendo assim, os objetivos gerais deste projeto foram:
1) Verificar e comparar a expressão gênica da ADAM10 em amostras de sangue entre sujeitos com TNCL, DA e sem alteração cognitiva;
2) Verificar e comparar a expressão gênica de miRNAs em amostras de sangue entre sujeitos com DA e sem alteração cognitiva;
3) Verificar se existe relação entre os níveis de mRNA para a ADAM10 e a expressão de miRNAs, visando fortalecer o papel da ADAM10 como molécula biomarcadora para a DA.
REFERÊNCIAS
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Manuscritos
4. MANUSCRITOS
4.1 MANUSCRITO I – Publicado
aDepartment of Gerontolgy, gDepartment of Physiological Sciences, hDepartment of
Medicine, Federal University of São Carlos, São Carlos, SP, Brazil
bDepartment of Pharmacological and Biomolecular Sciences,University of Studies of Milan,
Milan, Italy
cDepartment of Clinical and Experimental Science, Neurology Unit, University of Brescia,
Brescia, Italy
dNetherlands Institute for Neuroscience - an Institute of the Royal Netherlands Academy of
Arts and Sciences, Amsterdam, The Netherlands
eSwammerdam Institute for Life Sciences, Center for Neuroscience, University of
Amsterdam, Amsterdam, The Netherlands
fDepartment of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical
Center Utrecht, The Netherlands
* These authors equally contributed to this work
Corresponding Author: Márcia Regina Cominetti, Departamento de Gerontologia,
Universidade Federal de São Carlos, Rodovia Washington Luís, Km 235, São Carlos, SP, 13565-905, Brazil, phone: +55 16 3306 6663, fax +55 16 3351 9628. E-mail:
mcominetti@ufscar.br
Manuscritos
Abstract
ADAM10 is a potential biomarker for Alzheimer´s disease (AD). ADAM10 protein levels are reduced in platelets of AD patients. The aim was to verify the total blood and platelet ADAM10 gene expression in AD patients and to compare with mild cognitive impartment (MCI) and healthy subjects. No significant differences in ADAM10 gene expression were observed. Therefore, the decrease of ADAM10 protein in platelets of AD patients is not caused by a reduction in ADAM10 mRNA. Further studies must be performed to investigate other pathways in the down regulation of ADAM10 protein.
Manuscritos
1. Introduction
The pathological features in Alzheimer’s disease (AD) brain include cortical atrophy, predominantly in the medial temporal lobe and, microscopically, extensive neuronal loss and abnormal extra and intracellular fibrillar deposits, termed senile plaques and neurofibrillary tangles, respectively (Hohsfield and Humpel, 2015). The senile plaques appear from excessive deposition and subsequent aggregation of -amyloid peptide (A ) in the brain. AD pathogenesis is multifaceted and difficult to pinpoint, however genetic and cell biology studies led to the amyloid hypothesis, which posits that A plays a pivotal role in AD pathogenesis (Hardy and Selkoe, 2002). A derives from the concerted action of BACE1 ( - secretase) and the -secretase complex on the Amyloid Precursor Protein (APP) (Lichtenthaler, 2011). In healthy subjects the predominant route of APP processing consists of successive cleavages by and -secretases. In the non-amyloidogenic pathway, APP is cleaved by -secretases between lysine16 and leucine17 in the middle of A region, thus releasing sAPP - a structure with neurotrophic and neuroprotective functions (Meziane et al., 1998, Stein et al., 2004) retaining the C83 residue in the membrane. The following cleavage of C83 by -secretase releases the p3 - which is supposed to be beneficial, and is not found in amyloid plaques - and starts at position A 17 (A 17-40 and A 17-42), thereby inhibiting amyloidogenic A production (Morishima-Kawashima and Ihara, 2002).
Several enzymes in the ‘‘a disintegrin and metalloprotease’’ (ADAM) family, including ADAM9, ADAM10, and ADAM17, have -secretase activity in vitro, although recent studies have demonstrated that ADAM10 is the major -secretase that catalyzes APP ectodomain shedding in the brain (Kuhn et al., 2010, Jorissen et al., 2010). Moreover, it has been demonstrated that ADAM10 is a susceptibility gene of late onset AD (LOAD), the most common form of the disease. Indeed, two rare highly penetrant nonsynonymous mutations associated with LOAD have been identified in ADAM10 prodomain (Kim et al., 2009).
In previous studies we have reported a marked reduction in ADAM10 platelet protein levels in CDR (Clinical Dementia Rating) subgroups compared to non-AD patients (Manzine et al., 2013, Colciaghi et al., 2002) and APP, BACE1 and ADAM10 alterations in platelets already in the very early stages of the disease in which dementia can be barely inferred by neuropsychological assessments (Colciaghi et al., 2004). Since ADAM10 is the most important -secretase involved in cleavage of APP, in this work we raise the following question: is ADAM10 protein reduction in blood of AD patients a consequence of a decrease in ADAM10 transcription? In order to answer this question, we assessed the expression of
Manuscritos
ADAM10 mRNA in total blood and in platelets of a selected population of AD, MCI and control subjects, using Reverse Transcription quantitative PCR (RT-qPCR).
2. Methods
2.1 Characteristics of the Subjects
Patients were recruited in reference (Public Center of Specialties) and counter- reference (Family Health Units) health services in Brazil and at the Department of Medical Sciences-Neurology (University of Brescia, School of Medicine - Italy). Subjects recruited for AD group were diagnosed with probable AD according to National Institute of Neurological Disorders and Stroke-Alzheimer Disease and Related Disorders Association (NINCS- ADRDA) criteria. For MCI group, subjects had CDR 0.5, MoCA (range 19-25), Pfeffer test without impairment and follow the Petersen criteria (Petersen, 2004). All participants underwent the exclusion criteria for head trauma, metabolic dysfunctions, haematological diseases, alcohol abuse, drug abuse, delirium, mood disorders, and treatment with medications affecting platelet functions, i.e., anticoagulants, antiplatelet drugs, serotoninergic agonists-